Transforming growth factor beta (TGFp) promotes epithelial differentiation and inhibits cell growth. Defects in TGFp signaling are common in cancer and frequently associated with reduced apoptosis and more aggressive tumor behavior. Though many TGFp signaling components function as tumor suppressors in breast, colon, and skin cancers, TGFp signaling in lung cancer is largely unexplored. My hypotheses are that defective TGFp signaling promotes tumor growth in LSCC and that specific TGFPsignaling defects are associated with distinct clinical tumor behavior and distinct tracheal epithelial cell behavior. I have observed frequent loss of TGFp signaling molecules in human LSCC samples. In Aim 1 I will define the spectrum and consequences of TGFp signaling defects in human LSCC. In Aim 2 I will use cultured tracheal epithelial cells to determine the effect of specific TGFp signaling defects on apoptosis, cell cycle arrest, migration, and endogenous TGFp production. In Aim 3 I will create a novel mouse model of LSCC to examine TGFp signaling in vivo. In summary, these studies examine how TGFp signaling defects modulate behavior of airway epithelial cells in vivo and in vitro and how these changes promote the growth of LSCC.